title: Novel modifications in the series of O-(2-phthalimidoethyl)-N-substituted thiocarbamates and their ring-opened congeners as non-nucleoside HIV-1 reverse transcriptase inhibitors.
abstract: The structure-activity relationships (SARs) of N-aryl-O-(2-phthalimidoethyl)thiocarbamates (C-TCs) and their imide ring-opened congeners (O-TCs) as non-nucleoside HIV-1 reverse transcriptase inhibitors were further investigated. The SAR strategy involved modifications of the N-phenyl ring followed by the hybridization of the most promising N-aryl and O-(2-phthalimidoethyl) substructures. The role of stereochemistry and tert-butyl substitution of the phthalimidoethyl moiety on activity was also investigated. Seventy-six analogues were prepared by parallel solution-phase synthesis. Twenty-two C-TCs displayed nanomolar activity against wild-type HIV-1 and a number of analogues were effective against the Y181C mutant. Compound 56 combined the highest activity so far identified against Y181C (EC(50)=1.3 microM) with good potency against the K103R mutant (EC(50)=4.8 microM). Docking simulations helped to rationalize the SARs.
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università di Genova, Viale Benedetto XV 3, I-16132 Genova, Italy. andrea.spallarossa@unige.it
authors.forename: Andrea
authors.initials: A
authors.lastname: Spallarossa
authors.forename: Sara
authors.initials: S
authors.lastname: Cesarini
authors.forename: Angelo
authors.initials: A
authors.lastname: Ranise
authors.forename: Olga
authors.initials: O
authors.lastname: Bruno
authors.forename: Silvia
authors.initials: S
authors.lastname: Schenone
authors.forename: Paolo
authors.initials: P
authors.lastname: La Colla
authors.forename: Gabriella
authors.initials: G
authors.lastname: Collu
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Sanna
authors.forename: Barbara
authors.initials: B
authors.lastname: Secci
authors.forename: Roberta
authors.initials: R
authors.lastname: Loddo
mesh_terms: D015195:Drug Design; D024882:Drug Resistance, Viral; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors*; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology* / Q000502:physiology; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D009705:Nucleosides / Q000737:chemistry; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013859:Thiocarbamates / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D009705:Nucleosides; D018894:Reverse Transcriptase Inhibitors; D013859:Thiocarbamates; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase